TFAP2A orchestrates gene regulatory networks and tubular architecture in kidney outer medullary collecting ducts
Janna Leiz, … , Christian Hinze, Kai M. Schmidt-Ott
Janna Leiz, … , Christian Hinze, Kai M. Schmidt-Ott
Published August 28, 2025
Citation Information: JCI Insight. 2025;10(19):e192361. https://doi.org/10.1172/jci.insight.192361.
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Research Article Cell biology Nephrology

TFAP2A orchestrates gene regulatory networks and tubular architecture in kidney outer medullary collecting ducts

Abstract

Mutations in the transcription factor TFAP2A are linked to congenital anomalies of the kidney and urinary tract in humans. While Tfap2a knockout (KO) in mouse collecting ducts leads to tubular epithelial abnormalities, its precise molecular functions in kidney tubules remain unclear. To investigate Tfap2a-dependent gene regulatory networks in the mouse kidney collecting ducts, we employed conditional KO (Hoxb7-Cre; Tfap2afl/fl) models combined with transcriptomics. Histomorphological and physiological assessments of Tfap2a-KO mice revealed progressive postnatal dilation of the outer medullary collecting ducts. Integrating bulk and single-nucleus RNA sequencing with in silico motif mapping in ATAC-seq datasets demonstrated that Tfap2a is highly expressed and active in normal collecting duct principal cells. Comparative transcriptomics between 3-month-old Tfap2a-KO and control mice identified dysregulated genes associated with cell adhesion and WNT signaling, including Alcam and Wnt9b. These changes were confirmed by in situ hybridization. Our findings reveal that Tfap2a regulates medullary collecting duct diameter by orchestrating a transcriptional network involving Wnt9b and Alcam, providing insights into its role in kidney structural integrity.

Authors

Janna Leiz, Karen I. López-Cayuqueo, Shuang Cao, Louisa M.S. Gerhardt, Christian Hinze, Kai M. Schmidt-Ott

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Figure 1

Transcription factors Tfap2a and Tfap2b show partly overlapping gene expression and gene activity in the adult kidney.

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Transcription factors Tfap2a and Tfap2b show partly overlapping gene exp...
(A) Uniform manifold approximation and projection (UMAP) embedding of multiomic sequencing data for mouse kidneys based on both RNA and ATAC data using a weighted nearest neighbor (wnn) analysis (27,802 nuclei, n = 3). Nuclei were annotated to podocytes (Podo), parietal epithelial cells (PEC), proximal tubule (PT) cells, thin limb (tL) cells, thick ascending limb (TAL) cells, distal convoluted tubule (DCT) cells, connecting tubule (CNT) cells, collecting duct principal cells (CD-PCs), collecting duct intercalated cells (CD-ICs), endothelial cells (ECs), interstitial cells (IntCs), and immune cells (ImCs) using known marker genes. (B) Gene expression domains of Tfap2a and Tfap2b in the kidney. Top: UMAP displaying expression domains of Tfap2a and Tfap2b mRNA in mouse kidneys. The color gradient ranges from gray (no expression) to dark blue (highest expression). CD-PCs were extracted and reclustered to identify subpopulations. Marker gene analysis enabled annotation as cortical CD (CCD), outer medullary CD (OMCD), or inner medullary CD (IMCD), which were then remapped onto the original UMAP to visualize their distribution within the global dataset. Bottom: In situ hybridization (RNAscope) for Tfap2a (left) and Tfap2b (right) mRNA (brown dots) in adult mouse kidney tissue. Expression was detected in the TAL, tL, macula densa (MD), distal tubule (DT; comprised of DCT and CNT), CCD, OMCD, and IMCD. Scale bars: 50 μm. (C) Chromatin accessibility of the Tfap2a and Tfap2b genes in cells of the kidney. Same UMAP as in B, displaying chromatin accessibility associated with the Tfap2a and Tfap2b genes as a color gradient ranging from gray (no accessibility) to dark purple (high accessibility).